tbuckley/cabot-search huggingface dataset:
Abstract B026: Simulations of cancer evolution predict relative benefits of synergistic and non-synergistic drug combinations for combating different landscapes of drug-resistance
Authors: Elysia Saputra, Lisa Tucker-Kellogg
Journal: Cancer Research (2022)

Abstract Cancer therapies often have short duration of success due to the development of drug-resistance, which motivates research into anti-evolutionary therapies. A popular strategy is to combine two drugs, particularly if they have synergistic (greater-than-additive) efficacy. However, therapies that cause synergistic suppression of drug-sensitive cells will also suffer from synergistic release of drug-resistant cells, when drug-resistance arises. Not yet understood is the impact of partial drug-resistance and semi-resistant phenotypes on the speed of clonal expansion under combination therapy. In this work, we perform computational modeling to compare the growth rates of heterogeneous populations of cells, when drug-resistance is a binary (all-or-nothing) phenotype, versus when it is a spectrum of partially-sensitive phenotypes. We ask whether the type and granularity of drug-resistance levels in the drug-resistance landscape affects the relative outcome of using synergistic versus non-synergistic drug combinations. We observe that if drug-resistance can develop via rapid, “plastic” phenotypic transitions, then synergistic drugs provide long-lasting suppression of resistance than additive drugs (when dosed to have equal initial efficacy). Conversely, if drug-resistance develops via slow acquisition of phenotypic changes (e.g., requiring multiple genomic lesions), then synergistic drugs promote faster evolution of drug-resistance than additive drugs. When studying how synergism affects evolution, we found that cells escaping a synergistic treatment would be more likely to develop “asymmetric resistance” toward one drug (with greater sensitivity toward the other drug). In contrast, cells escaping antagonistic treatments would be more likely to develop symmetric resistance (equal levels of resistance) toward both drugs. Our findings suggest that after a synergistic treatment, a post-relapse tumor would be more likely to retain sensitivity to one of the drugs used, compared with equivalent relapse after non-synergistic combination treatment. Thus, theoretical modeling can provide testable predictions that complement the hypotheses arising from experiments. Citation Format: Elysia Saputra, Lisa Tucker-Kellogg. Simulations of cancer evolution predict relative benefits of synergistic and non-synergistic drug combinations for combating different landscapes of drug-resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B026.
Neuropsychiatric Ramifications of Severe COVID-19 and Other Severe Acute Respiratory Infections
Authors: Ashley Kieran Clift, Tom Alan Ranger, Martina Patone, Carol A. C. Coupland, Robert Hatch, Karen Thomas, Julia Hippisley-Cox, Peter Watkinson
Journal: JAMA Psychiatry (2022)

Individuals surviving severe COVID-19 may be at increased risk of neuropsychiatric sequelae. Robust assessment of these risks may help improve clinical understanding of the post-COVID syndrome, aid clinical care during the ongoing pandemic, and inform postpandemic planning.
Therapeutic potential of targeting galectins – A biomaterials-focused perspective
Authors: Sergio Martin-Saldaña, Merari Tumin Chevalier, Abhay Pandit
Journal: Biomaterials (2022)

Among all the biological entities involved in the immune response, galectins, a family of glycan-binding proteins, have been described as key in immune cell homeostasis and modulation. More importantly, only some galectin family members are crucial in the resolution of inflammation, while others perpetuate the immune response in a pathological context. As they are expressed in most major diseases, their potential as targets for new therapies seems promising. Most of the galectin family members' ubiquitous expression points to the need for targeted treatments to ensure effectiveness. Engineered biomaterials are emerging as a promising method to improve galectin-targeted strategies' therapeutic performance. In this review, we provide an overview of the role of galectins in health and disease and their potential as therapeutic targets, as well as the state-of-the-art and future directions of galectin-targeted biomaterials.
Perspectives on Racism in Health Care Among Black Veterans With Chronic Kidney Disease
Authors: Kevin A. Jenkins, Shimrit Keddem, Selamawite B. Bekele, Karisa E. Augustine, Judith A. Long
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The burden of chronic kidney disease (CKD) and end-stage kidney disease falls disproportionately on Black individuals in the US, with Black veterans experiencing substantial consequences, and only a portion of the disparities in health conditions and health care can be explained by nonbiological factors. Among Black individuals, racism is likely one of those factors, suggesting the need to examine the consequences of racism and the resulting social structures that establish and perpetuate these racial disparities. <h3>Objective</h3> To investigate the health care experiences of Black veterans with CKD and identify and explore the racial discrimination encountered by this vulnerable population. <h3>Design, Setting, and Participants</h3> This qualitative study used semistructured interview guides to investigate the health care experiences of 36 Black veterans with CKD who received care at the Corporal Michael Crescenz Veterans Affairs Medical Center in Philadelphia, Pennsylvania, from October 2018 to September 2019. Interview transcripts were analyzed using applied thematic analysis. <h3>Results</h3> Among 36 Black veterans with CKD who characterized racism in the context of their care at a Veterans Affairs medical center, the mean (SD) age was 66.0 (7.8) years; 35 participants (97.2%) were male, 1 participant (2.8%) was female, and 19 participants (52.8%) were married. The mean (SD) duration of military service was 8.0 (7.0) years. Overall, 15 participants (41.7%) were not dependent on dialysis, and hypertension was the most common comorbidity (9 participants [25.0%]). Veterans described the ways in which racism produced emotional and physical stress, including psychological symptoms (eg, anger and hurt) and physiological symptoms (eg, headaches). Veterans described a strong sense of distrust in the health care system coupled with a need to be hypervigilant during clinical encounters. When encountering racism, veterans described bottling up their feelings, which sometimes led to maladaptive behavior (eg, substance use). Veterans also described individual and collective positive strategies (eg, faith) for coping with the stress of racism. <h3>Conclusions and Relevance</h3> In this study, Black veterans with CKD experienced racism in the clinical setting that produced physical and emotional stress and a strong sense of distrust in the health care system. These findings highlight an important opportunity for education and training of health care professionals in the implementation of trauma-informed approaches to care as a means of addressing race-based stress and trauma.
Using Registry Data to Fill Blind Spots From Randomized Trials of Abdominal Aortic Aneurysm Repair
Authors: Jesse A. Columbo, David H. Stone
Journal: JAMA Network Open (2022)

Kevin Yei, BS; Asma Mathlouthi, MD; Isaac Naazie, MD, MPH; Nadin Elsayed, MD; Bryan Clary, MD; Mahmoud Malas, MD, MHS
Effect of self-managed lifestyle treatment on glycemic control in patients with type 2 diabetes
Authors: Chinmay Dwibedi, Emelia Mellergård, Amaru Cuba Gyllensten, Kristoffer Nilsson, Annika S. Axelsson, Malin Bäckman, Magnus Sahlgren, Stephen H. Friend, Sofie Persson, Stefan Franzén, Birgitta Abrahamsson, Katarina Steen Carlsson, Anders H. Rosengren
Journal: npj Digital Medicine (2022)

Abstract The lack of effective, scalable solutions for lifestyle treatment is a global clinical problem, causing severe morbidity and mortality. We developed a method for lifestyle treatment that promotes self-reflection and iterative behavioral change, provided as a digital tool, and evaluated its effect in 370 patients with type 2 diabetes (ClinicalTrials.gov identifier: NCT04691973). Users of the tool had reduced blood glucose, both compared with randomized and matched controls (involving 158 and 204 users, respectively), as well as improved systolic blood pressure, body weight and insulin resistance. The improvement was sustained during the entire follow-up (average 730 days). A pathophysiological subgroup of obese insulin-resistant individuals had a pronounced glycemic response, enabling identification of those who would benefit in particular from lifestyle treatment. Natural language processing showed that the metabolic improvement was coupled with the self-reflective element of the tool. The treatment is cost-saving because of improved risk factor control for cardiovascular complications. The findings open an avenue for self-managed lifestyle treatment with long-term metabolic efficacy that is cost-saving and can reach large numbers of people.
Stereopure oligo therapy for ALS
Authors: John J. Rossi
Journal: Molecular Therapy (2022)

The first antisense oligonucleotide (ASO) approved for clinical use targeted cytomegalovirus (CMV) and was designed to treat CMV retinitis. Although this patient market is limited, it nevertheless triggered increased interest in the technology. Despite their versatility, phosphorothioate ASOs possess chirality at each nucleotide, resulting in less stable hybrids with their RNA complement. Thus, a 20-mer exists as hundreds of thousands of chiral forms that differ in activity, including the ability to hybridize to their target. This problem makes it difficult to specifically target disease messenger RNAs that have small base change mutations relative to the wild-type allelic version. Wave Life Sciences has tackled the problem of chirality with the recent development of stereopure ASOs with phosphoryl guanidine (PN)-containing backbone linkages. A recent publication in Molecular Therapy Nucleic Acids1 Liu Y. Andreucci A. Iwamoto N. Yin Y. Yang H. Liu F. Bulychev A. Hu X.S. Lin X. Lamore S. et al. Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD. Mol. Ther. Nucleic Acids. 2022; https://doi.org/10.1016/j.omtn.2022.04.007 Abstract Full Text Full Text PDF Scopus (7) Google Scholar tests this chemistry in a preclinical setting whereby they demonstrate that their stereopure ASO targeting the hexanucleotide repeat (WVE-004) selectively triggers degradation of repeat-containing transcripts both in amyotrophic lateral sclerosis (ALS) patient-derived motor neurons and in a transgenic mouse model of ALS.
Organ-specific endothelial cell heterogenicity and its impact on regenerative medicine and biomedical engineering applications
Authors: Max Urbanczyk, Aline Zbinden, Katja Schenke-Layland
Journal: Advanced Drug Delivery Reviews (2022)

Endothelial cells (ECs) are a key cellular component of the vascular system as they form the inner lining of the blood vessels. Recent findings highlight that ECs express extensive phenotypic heterogenicity when following the vascular tree from the major vasculature down to the organ capillaries. However, in vitro models, used for drug development and testing, or to study the role of ECs in health and disease, rarely acknowledge this EC heterogenicity. In this review, we highlight the main differences between different EC types, briefly summarize their different characteristics and focus on the use of ECs in in vitro models. We introduce different approaches on how ECs can be utilized in co-culture test systems in the field of brain, pancreas, and liver research to study the role of the endothelium in health and disease. Finally, we discuss potential improvements to current state-of-the-art in vitro models and future directions.
Results of Two Cases of Pig-to-Human Kidney Xenotransplantation
Authors: Robert A. Montgomery, Jeffrey M. Stern, Bonnie E. Lonze, Vasishta S. Tatapudi, Massimo Mangiola, Ming Wu, Elaina Weldon, Nikki Lawson, Cecilia Deterville, Rebecca A. Dieter, Brigitte Sullivan, Gabriella Boulton, Brendan Parent, Greta Piper, Philip Sommer, Samantha Cawthon, Erin Duggan, David Ayares, Amy Dandro, Ana Fazio-Kroll, Maria Kokkinaki, Lars Burdorf, Marc Lorber, Jef D. Boeke, Harvey Pass, Brendan Keating, Adam Griesemer, Nicole M. Ali, Sapna A. Mehta, Zoe A. Stewart
Journal: New England Journal of Medicine (2022)

Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue.We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection.The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m2 of body-surface area before transplantation to 62 ml per minute per 1.73 m2 after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m2 in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys.Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).
Annals Consult Guys - Physical Examination During Telemedicine Visits
Authors: Howard H. Weitz, Geno J. Merli
Journal: Annals of Internal Medicine (2022)

Web ExclusivesMay 2022Annals Consult Guys - Physical Examination During Telemedicine VisitsFREEHoward H. Weitz, MD and Geno J. Merli, MDHoward H. Weitz, MDThomas Jefferson University, Philadelphia, Pennsylvania (H.H.W., G.J.M.)Search for more papers by this author and Geno J. Merli, MDThomas Jefferson University, Philadelphia, Pennsylvania (H.H.W., G.J.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W21-0006 CME/MOC SectionsSupplemental MaterialAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The Annals Consult Guys discuss several physical examination findings that may (or may not) be useful when evaluating a patient via telemedicine.For more videos from and information on Annals Consult Guys, visit go.annals.org/ConsultGuys. Comments0 CommentsSign In to Submit A Comment Henrique HermidaUFMG24 May 2022 Excellent lecture Amazing presentation with so much useful information! As a medical student, I really appreciate this series! Thank you! Author, Article, and Disclosure InformationAffiliations: Thomas Jefferson University, Philadelphia, Pennsylvania (H.H.W., G.J.M.)Disclosures: Drs. Merli and Weitz report that they have no financial relationships or interests to disclose. All relevant financial relationships have been mitigated. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=W21-0006.Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Stephanie Chang, MD, MPH, Deputy Editor, reports employment with the Agency for Healthcare Research and Quality, travel compensation from the Guidelines International Network, and participation in the Patient-Centered Outcomes Research Institute methodology committee. Vineet Chopra, MD, MSc, Deputy Editor, reports grants received from the Agency for Healthcare Research and Quality and royalties from UpToDate and Oxford University Press. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interests to disclose. Eliseo Guallar, MD, MPH, DrPH, Deputy Editor, Statistics, reports that he is employed at Johns Hopkins University. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center and consultancy with Boston Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports employment with the Perelman School of Medicine, University of Pennsylvania, and consultancies with the U.S. Food and Drug Administration and the State of Colorado. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics May 2022Volume 175, Issue 5Page: CG1 ePublished: 17 May 2022 Issue Published: May 2022 CopyrightCopyright © 2022 by American College of Physicians. All Rights Reserved.Loading ...
Nonalcoholic fatty liver disease versus metabolic-associated fatty liver disease: Prevalence, outcomes and implications of a change in name
Authors: Cheng Han Ng, Daniel Q. Huang, Mindie H. Nguyen
Journal: Clinical and Molecular Hepatology (2022)

Nonalcoholic fatty liver disease (NAFLD) affects about a third of the world's adult population and is a major public health concern. NAFLD is defined by the presence of hepatic steatosis and the absence of other causes of liver disease. As NAFLD is closely associated with the presence of the metabolic syndrome, several experts have called for a change in nomenclature from NAFLD to metabolic-associated fatty liver disease (MAFLD) to better reflect the underlying pathophysiology of NAFLD as a metabolically driven disease and shift to a "positive" diagnostic criteria rather than one of exclusion. Recent studies have suggested that the global prevalence of MAFLD is higher than that of NAFLD, and patients with MAFLD have more metabolic comorbidities compared to those with NAFLD. Emerging data also suggest that all-cause and cardiovascular mortality may be higher in MAFLD compared with NAFLD. In this synopsis, we discuss differences in clinical features, prevalence and clinical outcomes between NAFLD and MAFLD. In addition, we highlight the advantages and disadvantages of a name change from NAFLD to MAFLD from the perspective of the scientific community, care providers and patients.
Association of Prior BNT162b2 COVID-19 Vaccination With Symptomatic SARS-CoV-2 Infection in Children and Adolescents During Omicron Predominance
Authors: Katherine E. Fleming-Dutra, Amadea Britton, Nong Shang, Gordana Derado, Ruth Link-Gelles, Emma K. Accorsi, Zachary R. Smith, Joseph Miller, Jennifer R. Verani, Stephanie J. Schrag
Journal: JAMA (2022)

Efficacy of 2 doses of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech) against COVID-19 was high in pediatric trials conducted before the SARS-CoV-2 Omicron variant emerged. Among adults, estimated vaccine effectiveness (VE) of 2 BNT162b2 doses against symptomatic Omicron infection was reduced compared with prior variants, waned rapidly, and increased with a booster.To evaluate the association of symptomatic infection with prior vaccination with BNT162b2 to estimate VE among children and adolescents during Omicron variant predominance.A test-negative, case-control analysis was conducted using data from 6897 pharmacy-based, drive-through SARS-CoV-2 testing sites across the US from a single pharmacy chain in the Increasing Community Access to Testing platform. This analysis included 74 208 tests from children 5 to 11 years of age and 47 744 tests from adolescents 12 to 15 years of age with COVID-19-like illness who underwent SARS-CoV-2 nucleic acid amplification testing from December 26, 2021, to February 21, 2022.Two BNT162b2 doses 2 weeks or more before SARS-CoV-2 testing vs no vaccination for children; 2 or 3 doses 2 weeks or more before testing vs no vaccination for adolescents (who are recommended to receive a booster dose).Symptomatic infection. The adjusted odds ratio (OR) for the association of prior vaccination and symptomatic SARS-CoV-2 infection was used to estimate VE: VE = (1 - OR) × 100%.A total of 30 999 test-positive cases and 43 209 test-negative controls were included from children 5 to 11 years of age, as well as 22 273 test-positive cases and 25 471 test-negative controls from adolescents 12 to 15 years of age. The median age among those with included tests was 10 years (IQR, 7-13); 61 189 (50.2%) were female, 75 758 (70.1%) were White, and 29 034 (25.7%) were Hispanic/Latino. At 2 to 4 weeks after dose 2, among children, the adjusted OR was 0.40 (95% CI, 0.35-0.45; estimated VE, 60.1% [95% CI, 54.7%-64.8%]) and among adolescents, the OR was 0.40 (95% CI, 0.29-0.56; estimated VE, 59.5% [95% CI, 44.3%-70.6%]). During month 2 after dose 2, among children, the OR was 0.71 (95% CI, 0.67-0.76; estimated VE, 28.9% [95% CI, 24.5%-33.1%]) and among adolescents, the OR was 0.83 (95% CI, 0.76-0.92; estimated VE, 16.6% [95% CI, 8.1%-24.3%]). Among adolescents, the booster dose OR 2 to 6.5 weeks after the dose was 0.29 (95% CI, 0.24-0.35; estimated VE, 71.1% [95% CI, 65.5%-75.7%]).Among children and adolescents, estimated VE for 2 doses of BNT162b2 against symptomatic infection was modest and decreased rapidly. Among adolescents, the estimated effectiveness increased after a booster dose.